Systemic lupus erythematosus (SLE or lupus) is a multi-organ, complex autoimmune disease with a substantial genetic component. Lupus is a significant health problem, and epidemiological reports indicate that it is at least 3 to 5 times more prevalent in people of African or Asian ancestry than Caucasian ancestry. Clinical manifestations and disease severity also vary significantly among different ethnicities. As of February 2010, genome-wide association studies (GWAS) and candidate gene studies have identified about 35 robust genetic associations (P<5x10-8) with lupus, mostly reported from European and some Asian (Chinese and Japanese) populations. Additionally, several recent reports demonstrated that some major genes associated with other autoimmune disease phenotypes are also associated with lupus susceptibility, suggests the existence of common shared autoimmunity genes. Although ~35 lupus susceptibility genes/regions are currently known, very few "functional" variants have been identified. We hypothesize that by simultaneously using a comprehensive fine-mapping and comparing the linkage disequilibrium (LD) pattern among multiple ethnic populations, we will be able to detect both robust and/or ethnic functionally relevant variants within SLE susceptibility genes. In this study, we propose to perform dense fine-mapping in a recently developed "ImmunoChip" using 2000 cases and 3000 controls from 4 ethnically diverse populations (European-American, African-American, Colombian, and Indian populations). The ImmunoChip will provide cost-effective fine- mapping using >196,000 selected single nucleotide polymorphisms (SNPs) from HapMap and 1000Genomes Project at 184 associated genomic regions associated with 12 autoimmune disease phenotypes, including 35 of recently identified and established (P<5x10-8) SLE susceptibility genes. We expect that many of these lupus associated genes will be replicated in multiple populations, and previously unknown functional variants within these genes will be discovered. Moreover, from the remaining 149 fine-mapped gene associated with other autoimmune phenotypes, we expect to identify several genes which also increase the risk of lupus. The goals of this proposal are to: (A) assess the robustness of genetic associations and detect functional variants in established susceptibility genes/regions for SLE and other inflammatory diseases, and (B) assess genetic associations with clinical sub-phenotypes of lupus. For each associated gene, we expect to identify a set of functional variants and their relative contributions that may be involved in the development of lupus in general or in a subset of patients. Ultimately, a comprehensive set of lupus associated functional variants made available through these experiments will provide a basis for future biological experiments to define how these functional variants contribute to the pathological mechanism in lupus. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus (SLE or lupus) is a significant global health problem. In the United States only, more than 2,000,000 individuals suffer from this devastating disease. The disease prevalence varies significantly from population to population, at least 3 to 5 times higher in people of African or Asian ancestry than Caucasian ancestry. The genetic basis of lupus is well established, and about 35 susceptibility genes are identified to date. The proposed study will attempt to identify a comprehensive set of lupus associated functional variants which may provide a basis for future biological experiments to define pathological mechanisms of lupus.